The antibacterial activities of 2-isocephem derivatives and 2-oxaisocephem derivatives are widely known [JP-A-211283/1988, J. Med. Chem., 31, 1190 (1988)]. Especially, 3-halomethyl derivatives thereof are important intermediates for preparing 3-alkenyl-2-isocephem derivatives and 2-oxaisocephem derivatives (JP-A-253008/1988, JP-A-31285/1991) which are nonnatural-type cephalosporin antibiotics, whereas reports have merely been made on several production examples of such derivatives up to date.
However, the production processes reported each have some problems, so that it has been desired to develop new production processes. For example, the processes have the following problems.
(1) The process disclosed in JP-B-32317/1986 and Can. J. Chem., Vol. 56, 1335 (1978) comprises treating a 2-azetidinyl-3,4-dihalogeno-2-butenoic acid compound with a base derived from carboxylic acid having pKa of 3.5 to 5.5 to obtain 3-acyloxymethyl-2-oxaisocephem derivative by ring closure, hydrolyzing the derivative to prepare a 3-hydroxymethyl-2-oxaisocephem derivative and treating the resulting derivative with a phosphorus halide to prepare a 3-halomethyl-2-oxaisocephem derivative as represented by the following reaction formula-1. The disclosed process results in a low yield, requires many reaction steps and uses a phosphorus compound having environmental problems such as a stringent waste water regulation.
(Reaction formula-1) ##STR2##
(2) The process disclosed in J-A-31285/1991 and J. Med. Chem., 31, 1190 (1988) wherein an azetidinone derivative having hydroxymethyl at the 4-position is tert-butyldimethylsilylated and then enolized with lithiumbistrimethylsilylacetamide, followed by a reaction with halogenated acetyl chloride and then by MITSUNOBU reaction (dehydration condensation reaction using an azodicarboxylic acid ester and triphenylphosphine) for ring closure uses expensive reagents, requires a cryogenic temperature, includes many steps and is therefore industrially infeasible.
(Reaction formula-2) ##STR3##
Thus, processes still remain to be developed which are free of all the problems about economy, yield, safety, work environment, etc.
An object of the present invention is to provide a novel cephem derivative production process for preparing a 3-halomethyl-2-isocephem derivative or 3-halomethyl-2-oxaisocephem derivative by a single step from a 2-azetidinyl-3,4-dihalogeno-2-butenoic acid compound represented by the general formula (1) and easily available, effectively utilizing the halogen atom at the 4-position.